Method of producing dihydro follicular hormones



Patented Mar. 2, 1937 UNITED STATES PATENT OFFICE METHOD OF PRODUCING DIHYDRO FOLLICULAR HORMONE-S Erwin Schwenk, Montclair, N. 3., and Bradley Whitman, New York, N. Y., assignors, by mesne assignments, to Schering Corporation, Bloomfield, N. J., a corporation of New Jersey No Drawing. Application November 29, 1935,

Serial No. 52,084. 1934 In Germany November 29,

13 Claims. (CL 280-154) the zeta group also can take place with the aidoi sodium and alcohol. The reaction product obtained according to the known processes, however,

always contains substances resulting from the introduction of more than two hydrogen atoms 15 into the molecule. thereby destroying the phenolic character the first ring. These more highly hydrogenated substances are insoluble in alkali, whereas the dihydro follicular hormone, containing-'as it does a phenolic group, is alkali-soluble. I'he'productIon of these more highly saturated compounds obviously reduces the yield of dihydro follicular hormone. Furthermore, in the case of the most important of the follicular hormones, namely, theelin, the alkali-soluble part obtained 25 by these known processes consists of a mixture of the isomers, whereas only the lower melting substance has been found in ovaries (Doisy and coworkers) and is the one that is the more desirable.

We have now found that much better yields of the dihydro compolmds can be obtained in a simple and convenient mannerby carrying out the reduction of the follicular hormones in alkaline solution and by employing for the development of hydrogen such non-alkali metals or alloys of non-- alkali metals as react with water or with alkaline solutions to produce hydrogen either at room temperatures; or at temperatures up to boiling. we have found that very suitable metals for this purpose are,'ior example, aluminium and magnesium 40 in a state of fine subdivision. Particularly good results are obtained with alloys made by melting together, for example, nickel and aluminium or nickel and silicon.

The reaction products obtained by such procedure are in a high state of purity, practically none of the more highly hydrogenated compounds being formed; and in the case of theelin, the product contains practically only the lower melting isomer.

Our improved mode of treatment can also be employed for crude natural and synthetic products containing the hormone to be reduced mixed with other substances. the dihydro compounds 5| being isolated by fractional crystallization, by extraction from specific solvents with alkali, or in any other known manner.

The invention will be described with the aid of the following examples which, however, are presented merely for purposes of illustration and not by way of limitation:

Example 1 5 grams 01' a crude product obtained in the usual manner from the urine of pregnant mares having a potency of 300,000 mouse units per gram, are dissolved with the aid of heat in two liters of a 5% water solution of NaOH, the insoluble material being filtered ofl. Finely powdered aluminium metal is then introduced in small portions into the filtrate. Some drops of a. solution of mercuric chloride in water may be added to accelerate the reaction of the aluminium with water. The reaction is continued, preferably at elevated temperatures, as long as the characteristic reactions of the keto group can be detected with samples taken from the reaction liquor. The small quantity of insoluble material which is precipitated is filtered oil. and the solution is then worked up in the usual manner by acidification and extraction or by isolation of the hormone in the form of an ester by subsequent reaction with an acid chloride, for example, benzoyl chloride.

Example 2 or alloy consisting of nickel and aluminium. The

solution, which is thoroughly agitated during the introduction of the catalyst, slowly warms up and the liberation of hydrogen becomes noticeable. If necessary, the solution may be chilled to avoid too vigorous a reaction. When the reaction is completed, the precipitated nickel is filtered oil and the dihydro follicular hormone is precipitated from the completely colorless mother liquor byacidification. The yield is almost quantitative, the melting point of the crude product being I'm-174 0., while the recrystallized product melts at 174 C.

Example 3 100 mg. oi equilenin (the natural product or produced synthetically, for example, from the de- C18Hl802 (equilenin),

hydrogenation product of neoergosterol (Honigmann, Annalen, 1935, vol. 511, page.292) or from dihydro equilenin is isolated by filtering.

As will be apparent to those skilled in the art, the specific proportions and conditions indicated above can be varied within the scope of the appended claims without departing from the spirit 'of the invention. It is necessary'only that those reagents and those conditions be employed which yield only a mild generation of hydrogen or hydrogen in a mild state of reactivity .to the end that only the ketone group is reduced to an alcoholic hydroxy group, the first or aromatic ring remaining substantially unattacked and retaining its female hormone property contributing characteristics.

We desire it to be understood that where we employ the term follicular hormones such term is not to be construed. as indicative of origin but rather of chemical nature and of physiological activity similar to that of the naturally occurring substances, our process being applicable to substances generally, regardless of their origin, whether animal, vegetable, or synthetic, having the properties of the female hormones and possessing in their molecule an unsaturated ring and a ketone group.

It will be seen from the above that our process can be employed generally for the partial hydrogenation of female hormones of various lnnds having an unsaturated benzene ring and. having a phenolic as well as a ketonic'oxygen atom, the number of hydrogen atoms varying from 18 to 22 both inclusive, as represented by the formulas CiaHaoOz (equilin) and C18H2202 (oestrone or theelin) We claim:

1. The method of reducing the keto group of a keto cyclopentano phenanthrene compound having an unsaturated first ring while leaving such ring substantially unattacked, which comprises dissolving such compound in an aqueous alkaline solution, and then adding thereto a nonalkali metal capable of generating hydrogen in such solution.

2. The method according to claim 1 wherein the hydrogen generating metal is an aluminium v alloy of the type known as Raney alloys.

3. The method of reducing the keto group of a keto cyclopentano phenanthrene compound. having an unsaturated first ring while leaving such ring substantially unattacked, which comprises dissolving such compound in an aqueous sodium hydroxide solution, and then adding thereto a fi'nely divided metal capable of generating hydro-.

gen relatively slowly in said solution and comprised within the group consisting of non-alkali met als'and their alloys.

4. The method of producing compounds hav- 1 ing the physiological activity of dihydro follicular group is hydrogenated.

alkaline solution to the action of a member of the group consisting of finely divided non-alkali metals and their alloys which develop hydrogen in such solution.

5. The method of producing dihydro follicular hormones which comprises subjecting an aqueous alkaline solution of" a ketonic female sexual hormone to the action of a member of the group consisting of finely divided metals and their alloys which develop hydrogen in aqueous alkaline solutions of such activity that only the ketone 6. The method of producing dihydro-follicular hormones which comprises subjecting an aqueous alkaline solution of a follicular hormone to the action of a member of the group consisting of finely divided non-alkali metals and their alloys which develop hydrogen in aqueous alkaline solutions.

'7. The method of producing dihydro follicular hormones which comprises subjecting an aqueous alkaline solution of a follicular hormone to the action of finely divided aluminium.

, hormones which comprises subjecting an aqueous sodium hydroxide solution of a follicular hormone to the action of a member of the group consisting of finely divided non-alkali metals and their alloys which develop hydrogen in aqueous alkaline solutions.

10. The method of producing dihydro follicular hormones which comprises subjecting unsaturated cyclopentano phenanthrene compounds, having the general formula CmILOz, one 0 being ketonic 11. The method of reducing the keto group off a follicular hormone which comprises dissolving such hormone in an ammoniacal solution, adding magnesium to such solution to cause generation of hydrogen, and then acidifying the solution to separate the dihydro hormone. 12. The method of reducing the keto group of a keto cyclopentano phenanthrene compound having an unsaturated first ring while leaving such ring substantially unattacked, which comprises dissolving such compound in an alkaline solution, and then adding thereto a non-alkali metal capable of generating hydrogen in such solution.

13. The method of producing dihydro follicular hormones which comprises subjecting unsatu rated cyclopentano phenanthrene compounds, having the general formula CHI-1202, one 0 being ketonic and the other phenolic and a: being an J even number from 18 to 22 both inclusive, to hydrogenation, by'means of analkaline solution and a member of the group consisting of nonalkali metals and their alloys which develop hydrogen in an alkaline solution.

BRADLEY WHITMAN. 

